This research program aims to develop an effective drug to prevent the development of the acute respiratory distress syndrome (ARDS) caused by systemic inflammatory states. ARDS is initiated by numerous systemic mediators of inflammation (eg cytokines and eicosanoids), and finalized with lung damage caused by proteolytic enzymes released from activated neutrophils. Previous clinical trials of drugs to prevent or treat ARDS have been disappointing, perhaps in part because their focus has been on blocking a single inflammatory initiator. A preferred strategy would be to inhibit neutrophil proteases which are the specific effector of tissue damage. Our lead compound, COL-3, possesses a broad spectrum of anti-protease activity. COL-3 in animal models has high efficacy and an optimal profile of activity against the most active and damaging enzymes in ARDS - matrix metalloproteinases and neutrophil elastase. Preliminary data from our laboratories indicates that COL-3 can reduce lung injury and mortality in acute animal models of ARDS. We now propose to study the efficacy of COL-3 in preventing ARDS under conditions that more closely resemble the human disease - sepsis-induced ARDS in an insidious onset animal model. Thus our specific aim is to: * Determine the efficacy of COL-3 in preventing lung injury and death in a clinically relevant model of ARDS. The long term goal is to bring to market a novel, effective drug that will have world-wide applicability as a safe, low cost, and effective treatment for the adult respiratory distress syndrome. PROPOSED COMMERCIAL APPLICATIONS: Over 100,000 patients are affected by ARDS yearly, with a mortality of over 40% and high morbidity and medical costs. Despite significant advances in intensive care management mortality has improved only 10% over the last decade. Successful development of an effective drug which reduces the morbidity, mortality and medical costs would significantly improve patient care and reduce the cost of treatment.